The Polycomb repressor complex 2 (PRC2) is composed of the core subunits Ezh1/2, Suz12, and Eed, and it mediates all di- and tri-methylation of histone H3 at lysine 27 in higher eukaryotes. However, little is known about how the catalytic activity of PRC2 is regulated to demarcate H3K27me2 and H3K27me3 domains across the genome. To address this, we mapped the endogenous interactomes of Ezh2 and Suz12 in embryonic stem cells (ESCs), and we combined this with a functional screen for H3K27 methylation marks. We found that Nsd1-mediated H3K36me2 co-locates with H3K27me2, and its loss leads to genome-wide expansion of H3K27me3. These increases in H3K27me3 occurred at PRC2/PRC1 target genes and as de novo accumulation within what were previously broad H3K27me2 domains. Our data support a model in which Nsd1 is a key modulator of PRC2 function required for regulating the demarcation of genome-wide H3K27me2 and H3K27me3 domains in ESCs.

聚梳阻遏物复合物2（PRC2）由核心亚基Ezh1 / 2，Suz12和Eed组成，它介导高级真核生物中赖氨酸27处组蛋白H3的所有二甲基和三甲基化。然而，关于如何调节PRC2的催化活性以划定整个基因组中的H3K27me2和H3K27me3域的了解甚少。为了解决这个问题，我们在胚胎干细胞（ESC）中绘制了Ezh2和Suz12的内源性相互作用基因组，并将其与H3K27甲基化标记的功能性筛选相结合。我们发现Nsd1介导的H3K36me2与H3K27me2共同定位，并且其丢失导致H3K27me3在全基因组范围内扩展。H3K27me3的这些增加发生在PRC2 / PRC1目标基因上，并且从头开始在以前广泛的H3K27me2域中积累。我们的数据支持一个模型，其中Nsd1是PRC2功能的关键调节剂，PRC2功能是调节ESC中全基因组H3K27me2和H3K27me3域划分所需的。